3-amino-1-diazacycloalkyl-alkyl-guanidines



United States Patent 3,178,433 S-AMHNO-l-DIAZACYCLOALKYL-ALKYL-GUANlDlNES Robert Paul Mull, Florham Park, N.J., assignor to CibaCorporation, New York, N.Y., a corporation of Delaware No Drawing. FiledMay 7, 1963, Ser. No. 273,750

8 Claims. (Cl. 260268) The present invention concerns amino-guanidines.More especially, it relates to l-R-lower alkyl-S-amino guanidines, inwhich R represents N,N-(N-R -aza-alkylene)-imino having from four to sixcarbon atoms as chain members, and R representing an organic radical,salts or acyl derivatives of such compounds, as well as to process forthe preparation of these compounds.

An N,N-(N-R -aza-alkylene)-imino group may be represented by theformula:

cnnm cin in which each of the letters m and m represents one of thenumbers 1 and 2, and R has the previously-given meaning. Such N,N-(N-R-aza-alkylene)-irnino radical are represented, for example, by 4-R-1-piperazino, l- N,N(3-R -3-aza-1,6-hexylene)imino, l-N,N-(4-R -4-aza-1,7-heptylene -imino, l-N,N-(3-R -3-aza-1,7-heptylene) imino and thelike, in which R has the previously-given meaning, and analogousradicals.

Attached to the aza-nitrogen atom of an N,N-(N-Rraza-alkylene)-iminogroup, is an organic radical R which represents primarily an aliphaticradical, and especially lower alkyl having from one to seven, preferablyfrom one to four, carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, secondary butyl, tertiary butyl and the like, as wellas n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl and thelike, as well as lower alkenyl, preferably allylic lower alkenyl havingfrom three to five carbon atoms, e.g. Z-propenyl (or allyl),2-methyl-2-propenyl (or 2-methyl-allyl), Z-butenyl (or 3-methyl-allyl)and the like, lower alkynyl, e.g. ethynyl, l-propynyl and the like, acycloaliphatic radical, particularly cycloalkyl having from three toseven, particularly from five to six, ring carbon atoms, e.g.cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like,cycloalkenyl having from five to seven ring carbon atoms, eg.2-cyclopentenyl, 3-cyclohexenyl and the like, or any other suitablealiphatic radical.

The above-mentioned aliphatic, particularly lower al kyl, groupsrepresenting R in the above formulae may be substituted, for example, byother aliphatic radicals, such as cycloaliphatic groups, primarily bycycloalkyl and cycloalkenyl as defined hereinabove, carboxylic aryl,particularly monocyclic or bicyclic carbocyclic aryl, e.g. phenyl,l-naphthyl or Z-naphthyl, as well as substituted phenyl, substitutedl-naphthyl or substituted Z-naphthyl. substituents attached to thecarbocyelic radicals are, for example, lower alkyl, e.g. methyl, ethyland the like, lower aikoxy, e.g. methoxy, ethoxy andthe like, loweralkylenedioxy, e.g. methylenedioxy and the like, lower 3,178,433Patented Apr. 13, 1965 alkylmercapto, e.g. methylmercapto,ethyl-mercapto and the like, nitro, amino, particularlyN,N-di-substituted amino, such as N,N-di-lower alkyl-amino, e.g.N,N-dimethylamino, N,N-diethylamino and the like, halogeno, e.g. fluoro,chloro, bromo and the like, trifluoromethyl or any other suitablesubstituent. Groups attached to carbocyclic portions may be in any ofthe available positions, whereby one or more than one of the same or ofdiiferent substituents may be present. Other substituents attached to analiphatic, particularly a lower alkyl, group are heterocyclic arylradicals, such as monocyclic azacyclic aryl, for example, pyridyl, e.g.Z-pyridyl, 3-pyridyl, 4-pyridyl and the like, bicyclic monocyclicazacyclic aryl, for example, quinolyl, e.g. 2-quinolyl and the like,monocyclic diazacyclic aryl, e.g. 3-pyridazinyl, Z-pyrimidyl, 4-pyrimidyl, Z-pyrazinyl and the like, monocyclic thiacyclic aryl, forexample, thienyl, e.g. 2-thienyl and the like, monocyclic oxacyclicaryl, for example, furyl, e.g. 2- furyl and the like. These heterocyclicaryl radicals may also have additional substituents, such as, forexample, those attached to the above-described carbocyclic radicals.

ticularly a lower alkyl radical may also be substituted by functionalgroups, such as, for example, hydroxyl, etherified hydroxy, such aslower alkoxy, e.g. methoxy, ethoxy, n-propyloxy, isopropyloxy,n-butyloxy, isobutyloxy and the like, polyalkylenedioxy, e.g.polyethylenedioxy, polypropylenedioxy and the like, whichpolyalkyleneoxy radicals may have from two to twenty lower alkyleneoxyportions and may have a free terminal hydroxyl group or an etherifiedterminal hydroxyl group, such as a terminal lower alkoxy, e.g. methoxy,ethoxy and the like, group, carbocyclic aryloxy, such as monocyclicearbocyclic aryloxy, e.g. phenyloxy and the like, or carbocyclicaryl-lower alkoxy, such as monocyclic carbocyclic aryl-lower alkoxy,e.g. benzyloxy, diphenylmethoxy, (4-chlorophenyl)-phenyl-methoxy and thelike, or esterified hydroxyl, such as lower alkoxy-carbonyloxy, e.g.methoxy-carbonyloxy, ethoxy-carbonyloxy and the like, carbamyloxy, suchas carbamyloxy, or N- lower alkyl-carbamyloxy, e.g. N-methyl-carbamyloxyand the like, N,N-di-lower alkyl-carbomyloxy, e.g.N,N-dimethyl-carbamyloxy and the like, or N-carbocyclic arylcarbamyloxy,particularly N-monocyclic carbocyclic aryl-carbamyloxy, e.g.N-phenyl-carbamyloxy and the like, or lower alkanoyloxy, e.g. acetoxy,propionyloxy and the like, or acyl groups, such as lower alkanoyl, e.g.acetyl and the like, amino, for example, unsubstituted amino,N-mono-substituted amino, for example, N-lower alkylamino, e.g.N-methylamino, N-ethylarnino and the like, N-carbocyclic aryl-amino,particularly N-monocyclic carbocyclic aryl-amino, e.g. N-phenylamino andthe like, N-carbocyclic aryl-lower aliphatic hydrocarbon amino,particularly N-rnonocyclic carbocyclic-lower alkyl-amino, such asN-phenyl-lower alkyl-amino, e.g. N-ben'zyl-amino,N-(2-phenylethyl)-amino and the like, or primarily N,N-disubstitutedamino, such as N,N-di lower alkyl-amino, in which lower alkyl has fromone to four carbon atoms, e.g. N,N-dimethylamino, N-ethylN-methyl-amino, N,N-diethylamino, N,N-di-n-propylamino,N,N-di-isopropylamino and the like, N-cycloalkyl- N-lower alkylamino,e.g. N-cyclopentyl-N-methylamino, N-cyclohexyl-N-ethylamino and thelike, N-lower alkyl- N-monocyclic carbocyclic aryl-amino, particularlyN- lower alkyl-N-phenyl-lower alkylamino, e.g. N-benzyl-N- methylamino,N-methyl-N-(Z-phenylethyl)-amiuo and the like, or N,N-alkyleneimino,N,N-oxa-alkyleneimino or N,N-aZa-alkyleneimino, in which alkylene hasfrom four to six carbon atoms as ring members, such as, for example,1-pyrrolidino groups, e.g. l-pyrrolidino, 2- methyl-l-pyrrolidino andthe like, l-piperidino radicals,

An aliphatic radical R in the above formulae, parawe ass e.g.l-piperidino, 2-methyl-l-piperidino, 3-methyl-l-piperidino,4-methyl-l-piperidino, B-hydroxy-l-piperidino, 3-acetoxy-l-piperidino,3-hydroxymethyl-l-piperidino and the like, 1-N,N-(l,6-hexylene)-imino,4-morpholino, or l-piperazino radicals, particularly 4-loweralkyl-l-piperazino, e.g. 4-methyl-l-piperazino, 4-ethyl-l-piperazino,4-(2-hydroxyethyl)-1-piperazino, 4-(2 acetoxyethyl)-1- piperazino,4-[2-(w-rnethoxy-polyethyleneoxy)-ethyl]-1- piperazino and the like,mercapto, etherified mercapto, especially lower alkyl-mcrcapto, e.g.methyl-mercapto, ethyl-mercapto and the like, halogeno atoms, e.g.fiuoro, chloro, bromo and the like, whereby one or more than onefunctional group may be attached to one or more than one carbon atom ofan aliphatic, particularly lower alkyl, radical.

The group R in the above formulae may also represent carbocyclic aryl,primarily monocyclic carbocyclic aryl, e.g. phenyl, or bicycliccarbocyclic aryl, e.g. lnaphthyl or Z-naphthyl, which radicals may haveone or more than one of the same or different substituents attached toany of the available carbon atoms; substituents are, for example, thosepreviously-described as being attached to a carbocyclic aryl radical. Italso represents heterocyclic aryl, primarily monocyclic or bicyclicheterocyclic aryl, which have one or more than one sulfur, oxygen and/ornitrogen atom as a ring member, such as, for example, monocyclicmono-azacyclic aryl, for example, pyridyl, e.g. Z-pyridyl, 3-pyridyl,4-pyridyl and the like, bicyclic mono-azacyclic aryl, for example,quinolyl, e.g. Z-quinolyl, 4-quinolyl and the like, monocyclicdi-azacyclic aryl, for example, pyridazinyl, e.g. 3-pyridazinyl and thelike, pyrimidyl, e.g. Z-pyrimidyl, 4-pyrimidyl and the like, pyrazinyl,e.g. 2-pyrazinyl and the like, pyrryl, e.g. 2-pyrryl and the like,monocyelic thiacyclic aryl, for example, thienyl, e.g. Z-thienyl and thelike, or monocyclic oxacyclic aryl, for example, furyl, e.g. Z-furyl andthe like, and these heterocyclic radicals substituted by substituents,such as, for example, those mentioned hereinbetore.

The lower alkyl radical, linking R with the aminoguanidino group, isrepresented by lower alkylene having from one to seven carbon atoms.Preferably, lower alkylene has from two to three carbon atoms, whichseparate the group R from the amino-guanidino group by the same numberof carbon atoms; such radicals are l,2-eth ylene, l-methyl- 1,Z-ethylene, Z-methyll ,Z-ethylene or 1,3-propylene. Other loweralkylene radicals are, for example, 2,3-butylene, 1,3-butylene,1,4-butylene, 1,4- pentylene, 1,5-pentylene and the like.

The 3-amino-guanidino group may be represented by the formula:

in which each of the groups R R R and R stands primarily for hydrogen,but may also represent an organic substituent, such as, for example, analiphatic group, particularly lower alkyl, e.g. methyl, ethyl, n-propyl,isopropyl and the like, as well as a carbocyclic aryl radical,particularly monocyclic carbocyclic aryl, e.g. phenyl, 'or phenylsubstituted by one of the previously-mentioned "substituents, or acarbocyclic aryl-aliphatic radical, such as monocyclic carbocyclicaryl-lower alkyl, particularly phenyl-lower alkyl, e.g. benzyl,l-phenylethyl, Z-phenylethyl, diphenylmethyl and the like, and analogousradicals in which the phenyl portion is substituted by any or thepreviously-described substituents. One of the groups R and R may alsorepresent an acyl radical, particularly the acyl radical of an organiccarboxylic acid, such as a lower aliphatic carboxylic acid, for example,a lower alkanoic acid, e.g. acetic, propionic, pivalic acid and thelike, a substituted lower alkanoic acid, e.g. chloroacetic,dichloroacetic, hydroxyacetic, methoxy-acetic, cyclopentyl-propionicacid and the like, or a lower alkanoic acid, e.g. 3-butenoic acid andthe like, a carboxylic aryl carboxylic acid, for example, a monocycliccarbocyclic aryl carboxylic acid, e.g. benzoic, hydroxybenzoic,4-methoxy-benzoic, 3,4-dimethoxy-benzoic, 3,4,S-trimethoxy-benzoic, 4 Oethoxycarboxylsyrnigic, 3,4-dichlorobenzoic,3-N,N-dimethylamino-benzoic, 4-nitrobenzoic acid and the like, or abicyclic carbocyclic aryl carboxylic acid, e.g. l-naphthoic, Z-naphthoicacid and the like, or a heterocyclic aryl carboxylic acid, for example,a monocyclic heterocyclic aryl carboxylic acid, e.g. nicotinic,isonicotinic, Z-furoic acid and the like. The amino-guanidino group ismore especially the group of the formula:

Salts of the new compounds of this invention are acid addition salts,particularly pharmaceutically acceptable, non-toxic acid addition salts,such as those with inorganic acids, e.g. hydrochloric, hydrobromic,sulfuric, phosphoric acids and the like, or with organic acids, such asorganic carboxylic acids, e.g. acetic, propionic, glycolic, lactic,pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric,citric, ascorbic, maleic, hydroxymaleic, dihydroxymaleic, fumaric,benzoic, phenylacetic, 4-aminobenzoic, 4-hydroxybenzoic, anthranilic,cinnamic, mandelic, salicylic, 4-aminosalicylic, Z-phenoxybenzoic,2-acetoxybenzoic acid and the like, or organic sulfonic acids, e.g.methane sulfonic, ethane sulfonic, 2-hydroxyethane sulfonic, p-toluenesulfonic acid and the like. Monoor poly-salts may be formed.

The new compounds of this invention and the salts thereof cause in theanesthesized, normotensive dog an inhibition of the carotid occlusionreflex pressor response and antagonize the pressor responses elicited byhigh doses of amphetamine, and lower the arterial pressure in theunanesthesized renal or neurogenic hypertensive dog. These effectsappear to be due to an inhibition of the release and/ or distribution oftransmitter substances from sympathetic nerve terminals. In view of thefact that the compounds of this invention block the hypertensive effectsof these pressor substances, they can, therefore, be used asantihypertensive agents to relieve hypertensive conditions, particularlythose of neuroginic, renal or essential nature. In addition, compoundsof this invention cause an increase in peripheral blood flow, and can,therefore, be used in functional peripheral vascular diseases, such asRaynauds disease and the like. The compounds are characterized by a fastonset of the pharmacological effects.

A preferred group of compounds of this invention are represented by thecompounds of the formula:

in which each of the letters m and M have the previously-given meaning,A represents lower alkylene having from two to three carbon atoms andseparating the amino-guanidino group from the N,N-N-R -aza-alkyleneiminogroup by two to three carbon atoms, and R stands for lower alkyl havingpreferably from one to four carbon atoms, c.g. methyl, ethyl, n-propyl,isopropyl, n-butyl and the like, and pharmaceutically acceptable,non-toxic acid addition salts thereof. Specific compounds of this groupare, for example,

3 -amino- 1 2- (4-methyll-piperazino) -ethyl] -guanidine,

3-amino-1 [3-(4-methyll-piperazino)-propyl] guanidine,

3-a1nino-1-[2-(4-ethyl-l-piperazino)-ethyl]-guanidine,

ene glycols or any other known carrier used in the manufacture of suchpreparations. The latter may be in solid form for example, as capsules,tablets, dragees and the like, or in liquid form, for example, assolutions, suspensions, emulsions and the like. If desired, they maycontain auxiliary substances, such as preserving, sfabilizing, wetting,emulsifying agents and the like, salts for varying the osmotic pressure,buffers, etc. They may also contain, in combination, other usefulsubstances.

The amino-guanidine compounds of this invention may be prepared, forexample, by converting in an R-lower alkyl-amine, in which R has theabove-given meaning, or a salt thereof, the amino group into anamino-guanidino group and, if desired, converting a resulting salt intothe free compound, and/ or, if desired, converting a resulting compoundinto a salt or an acyl derivative thereof.

The reagents of choice for the conversion of an amino group into anamino-guanidino group are S-lower alkyl- 2-isothiosemicarbazides,particularly those of the formula:

in which R R and R have the previously-given meaning, and R stands forlower alkyl, particularly methyl, as well as ethyl, n-propyl, isopropyland the like, and acid addition salts thereof. The salts, which areemployed in preference over the free base, are primarily those withmineral acids, e.g. hydrochloric, hydrobromic, hydriodic, sulfuric acidand the like. The preferred reagents are acid addition salts ofS-methyl-Z-isothiosemicarbazide with mineral acids, such as thehydrochloride, hydriodide, sulfate and the like. The starting material,in which the amino group is above all an unsubstituted amino group, butmay also represent a substituted amino group having R as thesubstituent, is generally used in the form of its free base.

The reaction is carried out by contacting the starting material with thereagent, preferably in the presence of an inert solvent, the choice ofwhich depends primarily on the solubility of the reactants. Water orwater-miscible organic solvents, such as lower alkanols, e.g. methanol,ethanol, propanol, isopropanol, tertiary butanol and the like, ethers,e.g. diethyleneglycol dimethyl-ether, p-dioxane, tetrahydrofuran and thelike, ketones, e.g. acetone, ethyl methyl ketone and the like, loweralkanoic acids, e.g. acetic acid and the like, formamides, e.g.formamide, N,N-dimethylformamide and the like, or aqueous mixtures ofsuch solvents represent the preferred diluents.

The reaction may be carried out at room temperature, or, if necessary,at an elevated temperature. Furthermore, it may be performed in theatmosphere of an inert gas, e.g. nitrogen, and/or in a closed vessel.

Analogous reagents capable of converting an amino group into anamino-guanidino group are the O-lower alkyl-2-isosemicarbazides,particularly those of the formula:

in which R R R and R have the previously-given meaning, or salts thereofwith mineral acids. These semicarbazide derivatives are used in the sameway as the above-described, corresponding l-amino-Z-isothioureareagents; an acid addition salt of O-methyl-Z-isosemicarbazide with amineral acid, e.g. hydriodic, sulfuric acid and the like, represents apreferred reagent.

The above-described reagents are known, or, if new, may be preparedaccording to procedures described in the prior art and used for themanufacture of known analogs; for example, the S-loweralkyl-2-isothiosemicarbazides or O-lower alkyl-Z-isosemicarbazides maybe manufactured by alkylating thiosernicarbazides or semicarbazides witha lower alkyl halide, e.g. methyl or ethyl chloride, bromide or iodideand the like or with a dilower alkyl-sulfate e.g. dimethyl sulfate,diethyl sulfate and the like.

The starting materials, i.e. the R-lower alkyl-arnines, in which R hasthe previously-given meaning, are known or may be prepared according toknown procedures. They may be obtained, for example, by treating acompound of the formula R--H, in which R has the previously-givenmeaning, with a halogeno-lower alkanonitrile, in which halogenorepresents, for example, chloro, bromo, and the like, or with a loweralkeno-nitrile, in which the double bond is activated by the nitrilegroup. In a resulting R-lower alkano-nitrile compound, the cyano groupis then converted into an aminornethyl group by reduction, for example,by catalytic hydrogenation, such as, treatment with hydrogen in thepresence of a catalyst containing a metal of the eighth group of thePeriodic System, e.g. palladium on charcoal, Raney nickel and the like,or, preferably, by treatment with a suitable light metal hydride, forexample, an aluminum hydride, e.g. lithium aluminum hydride, sodiumaluminium hydride, magnesium aluminum hydride, aluminium borohydride,aluminum hydride and the like, which hydrides may be used, if necessary,in the presence of an activator, such as aluminum chloride and the like.

The compounds of the present invention may also be prepared, forexample, by converting in a l-R-lower alkyl-S-X-guanidine, in which Rhas the previously-given meaning, and X stands for nitro or nitroso, ora salt thereof, the group X into an amino group, and, if desired,carrying out the optional steps.

The conversion of a nitro or a nitroso group into an amino group may becarried out by per se conventional reduction methods. For example,reduction may be achieved by treatment with nascent hydrogen; the lattermay be generated by contacting a suitable metal or metal compound with ahydrogen donor, for example, zinc or any other analogous metal, withacetic acid and the like, zinc acetate or any analogous metal compoundwith water or a moist solvent, or any other equivalent metalhydrogendonor combination, such as, for example, an alkali metal, e.g. sodiumand the like, in the presence of liquid ammonia, a lower alkanol and thelike. Treatment with hydrogen in the presence of a catalyst, e.g. nickeland the like, may also be employed in the above conversion of a nitro ora nitroso group into an amino group; reduction of a nitro-guanidinogroup in neutral or basic medium may first lead to the formation of anitroso-guanidino group, whereas reduction in an acidic medium yieldsdirectly the desired amino-guanidino group. The reduction procedure mayalso be carried out electrolytically.

The starting materials, which are new and intended to be included withinthe scope of this invention, may be prepared, for example, by reactingan R-lower alkyl-amine with an S-lower alkyl-1-nitro-2-isothiourea or anS-lower alkyl-l-nitroso-Z-isothiourea or an acid addition salt of suchreagents; the reaction may be carried out according to thepreviously-described treatment of an amine with a 1-amino-S-loweraikyl-2-isothiourea. The coiresponding O-lower alkyl-l-nitro-Z-isoureasor O-lower alkyl-l-nitroso-2-isoureas may be substituted for the2-isothiourea reagents.

Preferred l-(R-lower alkyl)-3-nitro-guanidines and 1- (R-loweralkyl)-3-nitroso-guanidines used as the starting materials are, forexample, those of the formulae:

oilin -H NHN0 in which R A and the letters m and m have the previouslygiven meaning, and the acid addition salts thereof. Specific startingmaterials of that type are, for example,

1- [2- (4-methyl1-piperazino -ethyl] -3-nitro-guanidine,

1- 3- 4-methyll -piperazino -propyl] -3-nitro-guanidine,

1- 2- 4-ethyll- *iperazino -ethyl] -3-nitro-guanidine,

1- 2- 4-isopropyll-piperazino) -ethyl] -3-nitro-guanidine,

1-{2- l-N,N-( 3-aza-3-methyl-hexamethylene -imino]ethyl}-3-nitro-guanidine,

l-{2-[1-N,N-(4-aza-4-methyl-heptamethylene)-imino]-ethy1}-3-nitro-guanidine and the like, and

l- [2- (4-1nethyll-piperazino -ethyl] -3-nitr-oso-gu anidine,

1- 3- (4-methyll -piperazino -propyl] -3-nitroso-g1anidine,

1- 2- (4-ethyll-piperazino -ethyl] -3-nitroso-guanidine,

1- [2- 4-isopropyll-piperazino) -ethyl] -3-nitro soguanidine,

1-{2-[1-N,N-(3-aza-3-methyl-hexarnethylene)-imino]-ethyl}-3-nitroso-guanidine,

1-{2-[ 1-N,N- (4-aza-4-methyl-heptamethylene -imino]ethyl}-3-nitroso-guanidine and the like, and

acid addition salts of such compounds.

The new compounds may be obtained in the form of the free compounds oras the salts thereof. A salt may be converted into the free compound inthe customary way, for example, by treatment with a strong alkalinereagent, such as aqueous alkali metal hydroxide, e.g. lithium hydroxide,sodium hydroxide, potassium hydroxide and the like, or a strongquaternary ammonium anion (hydroxy ion) exchange resin and the like. Afree base may be transformed into an acid addition salt thereof byreacting the latter with an appropriate inorganic or organic acid, suchas one of those outlined hereinabove; such reaction may be carried out,for example, by treating a solution of the base in a suitable solvent orsolvent mixture with the acid or a solution thereof and isolating thedesired salt. Salts of the polybasic compounds of this invention may beobtained, in which not all of the salt-forming basic groups participatein the salt formation. Such salts may then be treated with an acid inorder to form compounds, in which all or a greater number of the basicgroups take part in the salt t-formation.

Acyl derivatives of the compound of this invention, i.e. compounds ofthe previous formula, in which one of the groups R and R represents anacyl radical as defined hereinabove, may be prepared, for example, bytreating the amino-guanidine compound with the reactive derivative of acarboxylic acid, for example, with the halide,

e.g. chloride and the like, or the anhydride thereof. Such reaction maybe performed in the presence of an inert solvent, -f-or example, in ahydrocarbon, such as a lower alkane, e.g. pentane, hexane and the likeor a monocyclic carbocyclic aryl hydrocarbon, e.g. benzene, toluene,xylene and the like, or a tertiary organic base, such as a liquidpyridine compound, e.g. pyridine, oollidine and the like. Acylation mayalso be achieved in the absence of a solvent, for example, by treatingthe amino-guanidine compound or a salt thereof with the acylatingreagent, for example, acetic acid anhydride in a sealed tube.

The invention also comprises any modification of the general processwherein a compound obtainable as an intermediate at any stage of theprocess is used as starting material and the remaining step(s) of theprocess is (are) carried out as well as any new intermediates.

In the process of this invention such starting materials are preferablyused which lead to final products mentioned in the beginning aspreferred embodiments of the invention.

This is a continuation-in-part application of my application Serial No.116,246, filed June 12, 1961, which in turn is a continuation-in-partapplication of my application Serial No. 76,480, filed December 19,1960, and now abandoned.

The following examples illustrate the invention and are not to beconstrued as being limitations thereon. Temperatures are given indegrees Centigrade.

Example 1 A mixture of 10 g. of 2-(4-methyl-1-piperazino)-ethylamine and16.3 g. of S-methyl-Z-isothiosemicarbazide hydriodide in ml. of water isrefluxed for four hours and then concentrated to dryness. The residue,recrystallized from a mixture of ethanol and diethyl ether, yields the3-amino-l-[2-(4-methyl-1-piperazino)-ethyl] guanidine hydriodide of theformula:

Ego-N HI which melts at 169-172.

The starting material may be prepared as follows: f 0.4 g. ofchloroacetonitrile is added dropwise to a solutron of 133 g. of4-methyl-piperazine in 100 ml. of ethanol. The mixture is refluxed,stirred for two hours and allowed to stand overnight. The solution isconcentrated under reduced pressure, the residue is treated with 270 ml.of percent aqueous sodium hydroxide while cooling and then extractedwith ether. The ether phase is dried over solid sodium hydroxide, thesolvent is removed, and the residue fractionated to yield the4-methyl-piperazinoacetonitrile, B.P. 120-125 12 mm. The productsolidifies upon standing, M.P. 53-56.

A solution of g. of 4-methyl-piperazino-acetonitrile in 400 ml. ofanhydrous ether is added to 1000 ml. of anhydrous ether containing 19 g.of lithium aluminum hydride while cooling and stirring. The reactionmixture is then refluxed for 6 hours, allowed to stand overnight anddecomposed by successive addition of 17 ml. of water, 20 of 30 percentaqueous sodium hydroxide and 53 ml. of water. The mixture is filtered,the filtrate is evaporated and the residue is distilled to yield thedesired 2-(4-methyll-piperazino)-ethylamine, B.P. 92/ 16 mm.

Example 2 A mixture of 8.55 g. of 2-(4-methyl-l-piperazino)- ethylamineand 8.32 g. of S-methyl-Z-isothiosemicarbazide hydrochloride in 25 ml.of water is refluxed for 4 /2 hours. After the strong evolution ofmethyl-mercaptan subsides, the solution is concentrated under reducedpressure and the residual oil crystallizes on cooling. The 3-amino-l-[2-(4-methyl-I-piperazino) ethyl] guani-dine hydrochloride ofthe formula is purified by recrystallization from a mixture of ethanoland acetonitrile, M.P. 156-159; yield: 10.0 g.

Example 3 5.7 g. of 1-[2-(4-methyl-1-piperazino)-ethyl1-3-nitroguanidineand 8.5 g. of zinc dust are mixed in a mortar with water to form a thickpaste, which is then added to 2.5 ml. of acetic acid while stirring. Thetemperature is held between and during the mixing of the reagents and isthen allowed to slowly rise to room temperature. The reaction mixture iswarmed to 40 on the steam bath and held at that temperature for fifteenminutes. The solid material is filtered off, the filtrate isconcentrated under reduced pressure to yield an acetate salt of 3 amino1-[2-(4-methyl-1-piperazino)-ethyl]-guani dine, which is converted tothe product of the procedure described in Example 2 by treatment with 6N hydrochloric acid.

The starting material is prepared as follows: A mixture of 4.75 g. of2-(4-methyl-1-piperazino)-ethy1-amine and 3.6 g. ofS-methyl-l-nitro-Z-isothiourea in 100 ml. of ethanol is refluxed forfour hours. After cooling, the 1 [2(4-methyl-1-piperazino)-ethyl]-3-nitro-guanidine is filtered off andrecrystallized from ethanol.

In the above example, the 1-[2-(4-methyl-1-piperazine)- ethyl] 3nitro-guanidine may be replaced by 1-[2-(4- methyll-piperazino)-ethyl]-3-nitroso-guanidine which upon reduction with zincin acetic acid is converted into the 3 amino 1[2-(4-methyl-1-piperazino)-ethyl]- guani-dine.

What is claimed is:

1. A member selected from the group consisting of a l-R-loweralkyl-S-amino-guanidine, in which R is N,N- (N-R -aza-alkylene)-imino ofthe formula:

in which each of the letters m and m represents one of the numbers 1 and2, and R stands for lower .alkyl, and in which the amino-guanidino grouphas the formula:

NHNH2 and a pharmaceutically acceptable acid addition salt thereof.

2. A compound of the formula:

ennu -on, NH

mar e in which R is lower alkyl, each of the letters m and m stands for1, and A is lower alkylene having from two to three carbon atoms andseparating the amino-guanidino group from the ring-nitrogen atom by twoto three carbon atoms.

3. A pharmaceutically acceptable acid addition salt of a compound of theformula:

2)m 2 NH-NHg in which R is lower alkyl, each of the letters m and mstands for 1, and A is lower alkylene having from two to three carbonatoms and separating the amino-guanidino group from the ring-nitrogenatom by two to three carbon atoms.

4. 3 amino 1 [2-(4-methyl-1-piperazino)-ethyl]- guanidine hydriodide.

5. 3 amino 1 [2 (4-methyl-1-piperazino)-ethyl]- guanidine hydrochloride.

6. A member selected from the group consisting of a compound having oneof the formulae:

in which R stands for lower alkyl, each of the letters m and 111 standsfor one of the numbers 1 and 2, and A is lower alkylene having from twoto three carbon atoms and separating the nitroguanidino and thenitrosoguanidino group EfI'OIXl the ring-nitrogen atom by two to threecarbon atoms, and an acid addition salt thereof.

7. 1 [2 (4 methyl-1-piperazino)ethyl]-3-nitroguanidine.

8. 1 [2 (4 methyl-l-piperazino)-ethyl]-3-nitrosoguanidine.

References Cited by the Examiner UNITED STATES PATENTS 3,055,882 9/62Mull 260-239 3,055,883 9/62 Mull 260239 3,098,066 7/63 Mull 260-268 X3,101,336 8/63 James et al. 260268 IRVING MARCUS, Primary Examiner.

NICHOLAS S. RIZZO, WALTER A. MODANCE,

Examiners.

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF A 1-R-LOWERALKYL-3-AMINO-GUANIDINE, IN WHICH R IS N,N(N-R1-AZA-ALKYLENE)-IMINO OFTHE FORMULA:
 6. A MEMBER SELECTED FROM THE GROUP CONSISTING OF ACOMPOUND HAVING ONE OF THE FORMULAE: